Scar-mediated inhibition and CSPG receptors in the CNS.
Scar-mediated inhibition and CSPG receptors in the CNS.
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DOI：
10.1016/j.expneurol.2012.07.009
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发表时间：
2012-10
影响因子：
5.3
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Sharma K;Selzer ME;Li S
在成年哺乳动物中，切断的轴突在中枢神经系统（CNS）损伤后不会明显再生，这是由于发育决定的神经元内在生长能力和轴突伸长的细胞外环境的降低。由反应性瘢痕组织产生的硫酸软骨素蛋白聚糖（CSPG）是成熟CNS中生长限制环境的特别有效的贡献者。因此，克服富含CSPG的瘢痕的强烈抑制是CNS损伤后实现功能恢复的重要治疗目标。到目前为止，克服CSPG抑制的主要体内方法是用局部应用的软骨素酶ABC（ChABC）进行酶消化，但几个缺点可能阻止使用这种细菌酶作为患者的治疗选择。为了开发更有效的治疗方法来克服CSPG介导的轴突再生和/或发芽抑制，需要更好地理解CSPG作用的分子机制。由于其大尺寸和密集的负电荷，CSPG被认为通过空间相互作用非特异性地阻碍基质分子与其细胞表面受体的结合而起作用。虽然这可能是真的，但最近的研究表明，白细胞共同抗原相关（LAR）磷酸酶亚家族的两个成员，蛋白酪氨酸磷酸酶σ（PTPσ）和LAR，是以高亲和力结合CSPG并介导CSPG抑制作用的功能性受体。CSPG还可以通过结合两种髓鞘相关生长抑制剂受体Nogo受体1和3（NgR 1和NgR 3）发挥作用。如果得到证实，这将表明CSPG具有多种抑制轴突生长的机制，使其成为特别有效和困难的治疗靶点。CSPG受体的鉴定不仅对于了解疤痕介导的生长抑制很重要，而且对于开发新型和选择性疗法以促进中枢神经系统损伤（包括脊髓损伤（SCI））后轴突发芽和/或再生也很重要。
Severed axons in adult mammals do not regenerate appreciably after central nervous system (CNS) injury due to developmentally determined reductions in neuron-intrinsic growth capacity and extracellular environment for axon elongation. Chondroitin sulfate proteoglycans (CSPGs), which are generated by reactive scar tissues, are particularly potent contributors to the growth-limiting environment in mature CNS. Thus, surmounting the strong inhibition by CSPG-rich scar is an important therapeutic goal for achieving functional recovery after CNS injuries. As of now, the main in vivo approach to overcoming inhibition by CSPGs is enzymatic digestion with locally applied chondroitinase ABC (ChABC), but several disadvantages may prevent using this bacterial enzyme as a therapeutic option for patients. A better understanding of the molecular mechanisms underlying CSPG action is needed in order to develop more effective therapies to overcome CSPG-mediated inhibition of axon regeneration and/or sprouting. Because of their large size and dense negative charges, CSPGs were thought to act by non-specifically hindering the binding of matrix molecules to their cell surface receptors through steric interactions. Although this may be true, recent studies indicate that two members of the leukocyte common antigen related (LAR) phosphatase subfamily, protein tyrosine phosphatase σ (PTPσ) and LAR, are functional receptors that bind CSPGs with high affinity and mediate CSPG inhibitory effects. CSPGs also may act by binding to two receptors for myelin-associated growth inhibitors, Nogo receptors 1 and 3 (NgR1 and NgR3). If confirmed, it would suggest that CSPGs have multiple mechanisms by which they inhibit axon growth, making them especially potent and difficult therapeutic targets. Identification of CSPG receptors is not only important for understanding the scar-mediated growth suppression, but also for developing novel and selective therapies to promote axon sprouting and/or regeneration after CNS injuries, including spinal cord injury (SCI).